Cancer research has focused largely on understanding tumor biology, assuming that tumor characteristics mostly determine disease course. However, it is clear that host defense and psychophysiological mechanisms that influence host defense also play an important role in disease outcome. Host defense against cancer are modulated by the central nervous system, via behavior, innervation of immune organs, especially by the sympathetic nervous system (SNS), and neuroendocrine outflow. In this proposal we intend to study how hardwired and chemical networks mediate psychosocial-induced changes in prostate cancer growth and metastases using the RM-9 mouse reconstitution model. Since, prostate cancer is a disease of elderly men, and striking dysregulation of SNS, neuroendocrine, and immune functions occurs with aging, our study will address how aging affects the ability of these systems to affect tumor growth in old mice subjected to isolation stress. Specific aim 1 will characterize isolation-induced changes in tumor growth/ metastases in young and old mice after orthotopic injection of prostate cancer cells. Effects of isolation on tumor immunity, and SNS, hypothalmo-pituitary-adrenal (HPA) and gonadal activity will be assessed. Specific aim 2 will examine tumor immunity in RM-9 prostate tumor-bearing young and old mice. Specific aim 3 will study the role of the SNS on tumor growth/metastases and tumor immunity. Data from these studies will lead to the development of a psychosocial stress model for prostate cancer in aged mice to study: (1) mechanisms through which the SNS, HPA, and hypothalamo-pituitary gonadal axis interact to influence host defense against prostate cancer under conditions of social stress; and (2) neural-immune mechanisms that influence current treatment strategies in this disease. Research examining how psychophysiological interactions affect prostate cancer may eventually provide a better understanding of variance in disease outcome, and aid in the development of efficacious treatments for patients with advanced disease. [unreadable] [unreadable] [unreadable]